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Molecularly Targeted Radiosensitization of Human Prostate Cancer by Modulating Inhibitor of Apoptosis

Authors' Affiliations: Departments of ¹ Radiation Oncology, ² Internal Medicine, and ³ Urology, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan

Requests for reprints: Liang Xu, Division of Cancer Biology, Department of Radiation Oncology, University of Michigan Comprehensive Cancer Center, Room 4131, 1331 East Ann Street, Ann Arbor, MI 48109-0582. Phone: 734-615-7017; Fax: 734-615-3422; E-mail: liangxu{at}umich.edu.

Purpose: The inhibitor of apoptosis proteins (IAP) are overexpressed in hormone-refractory prostate cancer, rendering the cancer cells resistant to radiation. This study aims to investigate the radiosensitizing effect of small-molecule IAP inhibitor both in vitro and in vivo in androgen-independent prostate cancer and the possible mechanism of radiosensitization.

Experimental Design: Radiosensitization of SH-130 in human prostate cancer DU-145 cells was determined by clonogenic survival assay. Combination effect of SH-130 and ionizing radiation was evaluated by apoptosis assays. Pull-down and immunoprecipitation assays were employed to investigate the interaction between SH-130 and IAPs. DU-145 xenografts in nude mice were treated with SH-130, radiation, or combination, and tumor suppression effect was determined by caliper measurement or bioluminescence imaging. Nuclear factor-B activation was detected by luciferase reporter assay and quantitative real-time PCR.

Results: SH-130 potently enhanced radiation-induced caspase activation and apoptosis in DU-145 cells. Both X-linked IAP and cIAP-1 can be pulled down by SH-130 but not by inactive SH-123. Moreover, SH-130 interrupted interaction between X-linked IAP/cIAP-1 and Smac. In a nude mouse xenograft model, SH-130 potently sensitized the DU-145 tumors to X-ray radiation without increasing systemic toxicity. The combination therapy suppressed tumor growth more significantly than either treatment alone, with over 80% of complete tumor regression. Furthermore, SH-130 partially blocked tumor necrosis factor-- and radiation-induced nuclear factor-B activation in DU-145 cells.

Conclusions: Our results show that small-molecule inhibitors of IAPs can overcome apoptosis resistance and radiosensitize human prostate cancer with high levels of IAPs. Molecular modulation of IAPs may improve the outcome of prostate cancer radiotherapy.